Cellular and Tissue Pathogenesis

细胞和组织发病机制

• 批准号: 10221027
• 负责人: Roy Vincent Sillitoe
• 金额: $ 21.49万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-22 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221027
• 关键词: 3-Dimensional; Address; Adult; Affect; Anatomy; Animals; Architecture; Ataxia; Behavior; Behavioral; Biological Models; Birth; Brain; Cell model; Cells; Cellular Structures; Child; Child Health; Cognitive; Defect; Development; Diagnosis; Disease; Disease Outcome; Disease model; Drosophila genus; Electrons; Environmental Risk Factor; Epilepsy; Equipment; Faculty; Generations; Genetic; Genetic study; Goals; Histology; Human; Imaging technology; Individual; Induced pluripotent stem cell derived neurons; Infrastructure; Intellectual and Developmental Disabilities Research Centers; Intellectual functioning disability; Knowledge; Lead; Link; Medicine; Microscope; Microscopy; Modeling; Modernization; Molecular; Motivation; Motor; Mus; Nerve Degeneration; Neuroglia; Neurons; Organ; Organoids; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Personal Satisfaction; Phenotype; Population; Positioning Attribute; Postdoctoral Fellow; Rattus; Research Personnel; Research Project Grants; Resolution; Resources; Science; Services; Structure; Synapses; Techniques; Tissues; Training; Transmission Electron Microscopy; Work; behavioral outcome; brain abnormalities; brain tissue; cell type; clinical phenotype; cognitive function; college; confocal imaging; design; developmental disease; effective therapy; experience; experimental analysis; genome editing; grasp; human disease; human model; human tissue; imaging capabilities; imaging modality; improved; in utero; in vitro Assay; in vivo Model; induced pluripotent stem cell; innovation; mouse genetics; neural circuit; neural correlate; neuropathology; response; student training; synergism; tool; transmission process; two photon microscopy; two-photon

Intellectual and developmental disabilities (IDDs) are common and have a devastating impact on child health around the world. Unfortunately, there are no effective treatments for the vast majority of IDDs and our understanding of the pathogenic mechanism for majority of IDDs is incomplete. A major impediment to solving how to better treat IDDs is our limited knowledge of how cells and tissues are impacted in each IDD. As a direct response to this problem, we have assembled the Cell and Tissue Pathogenesis Core (CTP Core) to study how brain anatomy and its associated pathologies arise. Our guiding rationale is that, solving how brain structure is wired in typical development will place us in an ideal position to uncover how faulty brain circuits eventually disrupt the ability to perform different behaviors in IDDs. Indeed, the pathological consequences of altering brain development typically present as severe motor or cognitive difficulties in children. The goal of the CTP Core is to provide our IDDRC Investigators with a centralized resource for comprehensive pathological examination of tissue, high-resolution two-photon and confocal imaging, ultra-structure tracking by electron microcopy, and the generation and characterization of human disease cellular models that are relevant to IDDs. By combining human cellular models, such as iPSC-derived neurons or glia, with deep structural and functional phenotyping of how the brain is mis-wired in different diseases or disease models, the CTP Core will provide a unique opportunity to address how distinct genetic and environmental factors may impact the brain and lead to alterations in cellular structure, connectivity and function. To accomplish these goals, we have divided the CTP Core into three sub-Cores that operate in parallel, but with the common goal of resolving brain structure as it relates to function and disease. The Neuropathology Sub-Core provides expertise in neuronal tissue analysis from basic histology and transmission electron microscopy to in-depth circuit analysis; the Microscopy Sub-Core provides access and training to state-of-the-art confocal and two-photon microscopy; and the Human Disease Cellular Models Sub-Core provides expertise for studies requiring reprogramming, characterization and genome editing of human induced pluripotent stem cells (iPSCs) and their progeny derived from IDD patients. Therefore, a major feature of the CTP Core is investigator access to both classic and modern analytical techniques using human tissue, in vivo model systems such as mouse, rat, drosophila, and in vitro assays such as 3-dimensional brain organoids and neurons and glia derived from human iPSCs. The ultimate goal of the CTP Core is to forge new avenues to improve the behavioral outcomes of IDD by correcting brain function and restoring various motor and cognitive functions. The availability of major equipment such as transmission and two-photon microscopes, existing effective workflow of services, and the collective experience with many disease models highlight the arsenal of tools available to BCM IDDRC investigators.

智力和发育障碍（IDD）很常见，对儿童健康有毁灭性的影响 世界各地。不幸的是，对于绝大多数IDD和我们的 了解大多数IDD的病原机制是不完整的。解决的主要障碍 如何更好地治疗IDD是我们对每个IDD中细胞和组织如何影响细胞和组织的有限了解。作为 对此问题的直接响应，我们将细胞和组织发病机理（CTP核）组装到 研究脑解剖结构及其相关的病理如何出现。我们的指导理由是，解决了如何大脑 结构与典型开发有关将使我们处于理想位置，以发现脑电路有多么故障 最终破坏了在IDD中执行不同行为的能力。确实， 改变大脑发育通常是儿童严重运动或认知困难。目标的目标 CTP核心是为我们的IDDRC调查人员提供集中资源，以综合病理 检查组织，高分辨率两光子和共聚焦成像，超结构跟踪 微剖面，以及与人类疾病细胞模型的产生和表征 IDD。通过将人类细胞模型（例如IPSC衍生的神经元或神经胶质）结合，与深层结构和 大脑如何在不同疾病或疾病模型中误导大脑的功能表型，CTP核心将 提供一个独特的机会来解决不同的遗传和环境因素如何影响大脑 并导致细胞结构，连通性和功能的改变。为了实现这些目标，我们有 将CTP核心分为并联的三个子核，但要解决大脑的共同目标 与功能和疾病有关的结构。神经病理学子核提供了神经元方面的专业知识 组织分析从基本的组织学和透射电子显微镜到深入电路分析；这 显微镜子核为最先进的共聚焦和两光子显微镜提供了访问和训练。 人类疾病细胞模型子核为需要重编程的研究提供了专业知识， 人类诱导多能干细胞（IPSC）及其后代的表征和基因组编辑 来自IDD患者。因此，CTP核心的主要特征是研究者访问这两个经典 以及使用人体组织的现代分析技术，体内模型系统，例如小鼠，大鼠，果蝇， 以及源自人IPSC的三维脑器官和神经元和神经元等体外测定。 CTP核心的最终目标是建立新的途径，以改善IDD的行为结果 纠正大脑功能并恢复各种电动机和认知功能。大专业的可用性 设备，例如传输和两光子显微镜，现有的有效服务工作流以及 许多疾病模型的集体经验突出显示了BCM IDDRC可用工具的库 调查人员。